Substituted pyrroloquinoxalinones and diones

ABSTRACT

Substituted pyrroloquinoxalinones and diones, useful as anti-inflammatory and anti-thrombotic agents.

BACKGROUND OF THE INVENTION

Substituted quinoxalinones are known as anti-viral and inflammatoryagents: see for example, Great Britain Pat. No. 1,394,170 (DerwentAgdoc. 33957U) or Belgian Pat. No. 818,784 (Derwent Agdoc 3871W).Quinoxalinones of biological interest are also described by Acheson inJ. Chem. Soc., 4731 (1950). Substituted quinoxalines were suggested asanti-malarial compounds during World War II by the group working underthe direction of F. H. S. Curd--see for example J. Chem. Soc., 1260(1949). Cheeseman, J. Chem. Soc., 1804 (1955) has describedquinoxalinones and quinoxalindiones without, however, describing anyparticular utility therefor. Pyrroloquinoxalines are known in the art,but a majority of these art references are to linear molecules; thethree rings are in a line. For example,dodecahydropyrrolo[1,2-a]quinoxaline is mentioned in J. Am. Chem. Soc.,72, 2982 (1950); 2H-pyrrolo[2,3-b]quinoxaline is mentioned in J. Ind.Chem. Soc., 40, 358 (1963); and 6H-pyrrolo[2,3-g]quinoxaline isdescribed in Bio. Chem. J., 69, 59 (1958). Tetrahedron Letters, 1969,1581, Angew. Chem. Int. Ed. Engl., 1968, 751 and Chem. Pharm. Bull.,1970, 2065 also mention other linear pyrroloquinoxalines. One referencedescribes fused pyrroloquinoxalines; U.S. Pat. No. 3,813,392 whichdiscloses 3H-pyrrolo[1,2,3-de]quinoxaline-2-ones, useful as centralnervous system depressants.

A pyrrolo[1,2,3-ef][1,5]benzodiazepine [named as a1,4-diazepino(3,1-h,i)indole] was prepared by Maitlis, Proc. Chem. Soc.1957, 354.

SUMMARY OF THE INVENTION

This invention provides compounds of the formula: ##STR1## wherein R' isH or C₁ -C₃ alkyl; when taken singly, R² is H, C₁ -C₃ alkyl, C₁ -C₃alkoxy, .Iadd.F .Iaddend.or Cl and R³ is H; and

R² and R³ when taken together with the carbon atoms to which they areattached form a benzene ring;

R⁴ is H, Cl or F;

R⁵ is OH, H or phenyl;

Y is O or H₂ :

z is --CH₂ --CH₂ -- or --CHR⁶ -- wherein R⁶ is H or C₁ -C₃ alkyl.

When Z in Structure I is CHR⁶, the resulting structure is apyrroloquinoxalinone of Structure II below with the ring atoms numberedconventionally. ##STR2##

Wherein R', R², R³, R⁴, R⁵ and R⁶ and Y have the same meaning as hereinabove. In structure II, when Y is O, the resulting compound is a1-substituted (orunsubstituted)-6-phenyl-1H-pyrrolo[1,2,3-de]quinoxaline-2,5[3H,6H]-dione.When Y is H₂, the compounds are named as 1-substituted (orunsubstituted)-6-phenyl-1H-pyrrolo[1,2,3-de]quinoxalin-5[6H]-ones.

Compounds according to Formula I above in which R³ and R⁴, when takentogether with the carbon atoms to which they are attached form a benzenering, are named as 1H-pyrrolo[1,2,3-de]benzo(g)quinoxalines. Thenumbering system to be employed is illustrated in Formula III below.##STR3##

Compounds in which Z is --CH₂ --CH₂ are illustrated in Formula IV below:##STR4##

Wherein R', R², R³, R⁴, R⁵ and Y have the same meaning as herein above.When Y is O, the compounds are named as1-substituted-7-phenyl-1H-pyrrolo[1,2,3-ef][1,5]benzodiazepine-2,6(3H,7H)-diones.In the above formulae, when either R' or R², or R⁶ is C₁ -C₃ alkyl,methyl, n-propyl, or isopropyl is represented. When R² is C₁ -C₃ alkoxy,the following groups are represented: methoxy, ethoxy, n-propoxy, orisopropoxy.

The compounds of this invention are prepared by reacting aquinoxalinone, a quinoxaline, a benzodiazepinone, or abenzoquinoxalinone, with an α-chloro or an α-acetoxy-α (permissiblysubstituted)phenyl or α,α-diphenylacetyl halide. This reaction producesan amide on that quinoxaline nitrogen meta to the amide oxygen in thequinoxalinones or one of the two ring nitrogens in thetetrahydroquinoxalines. If an α-chloro acetyl derivative is formed, ringclosure is effectuated with polyphosphoric acid acid to yield apyrroloquinoxalindione. If any α-acetoxy amide is formed, the acetoxygroup is preferably removed first by alkaline hydrolysis, to yield anα-hydroxy-α-phenylacetyl amide. This amide can then by cyclized asbefore with polyphosphoric acid to yield a pyrroloquinoxalindione orbenzopyrroloquinoxalindione or pyrrolobenzodiazepinedione or the likering system. The starting materials for the above synthetic proceduresare readily available from the prior art, either being known as such orbeing available by the synthetic methods described therein.

Compounds containing alkyl groups at the C-3, C-8 or N-1 atoms of thequinoxaline ring system are in general prepared by a procedure whichemploys as starting materials, those compounds available from the priorart which have the alkyl group already in place.

Polyphosphoric acid is the condensing agent of choice employed informing the final pyrrolo derivative, but, as will be apparent to thoseskilled in the art, other condensing agents can be substituted for it.

This invention is further illustrated by the following specificexamples.

EXAMPLE 1 PREPARATION OF4-DIPHENYLCHLOROACETYL-3,4-DIHYDRO-1H-QUINOXALIN-2-ONE.

A solution was prepared containing 10 g. of3,4-dihydro-1H-quinoxalin-2-one, 9.6 g. of triethylamine in 700 ml. ofbenzene. A solution of 18 g. of α,α-diphenyl-2-chloroacetyl chloridedissolved in 150 ml. of benzene was added to the previous benzenesolution. The resulting reaction mixture was heated at refluxingtemperature for about 6 hours. A solid which separated during thereaction was separated by filtration. Removal of the solvent from thefiltrate yielded as a residue4-(α,α,-diphenyl-α-chloro)acetyl-3,4-dihydro-1H-quinoxalin-2-one formedin the above reaction. Recrystallization of this residue from benzeneyielded purified material melting at 171°-2° C.; yield=11.2 g.

Analysis Calc.: C, 70.12; H, 4.55; N, 7.43; Cl, 9.41; Found: C, 70.01;H, 4.50; N, 7.68; Cl, 9.15.

Other compounds makable by the above procedure include:4-(p-fluorophenyl-α-chloro)acetyl-3,4-dihydro-1H-quinoxalin-2-one;mp=128°-31° C. (from methanol).

4-(p-Chlorophenyl-α-chloro)acetyl-3,4-dihydro-1H-quinoxalin-2-one;mp=greater than 150° C. (from methanol).

Analysis Calc.: C, 58.33; H, 3.61; N, 8.36; Cl, 21.15; Found: C, 58.50;H, 4.39; N, 8.79; Cl, 20.52.

4-(α-Phenyl-α-chloro)acetyl-3,4-dihydro-1H-quinoxalin-2-one; mp=154°-6°C.

Analysis Calc.: C, 63.90; H, 4.36; N, 9.31; O, 10.64; Cl, 11.79; Found:C, 63.70; H, 4.17; N, 9.49; O, 10.90; Cl, 11.83.

EXAMPLE 2 PREPARATION OF6-PHENYL-1H-PYRROLO(1,2,3-de)QUINOXALINE-2,5(3H,6H)-DIONE.

About 18 g. of4-(α-phenyl-α-chloro)acetyl-3,4-dihydro-1H-quinoxaline-2-one were mixedwith 250 g. of polyphosphoric acid. The mixture was heated at about 110°C. for 5 hours and was then poured into 2000 ml. of water. A solidprecipitate was separated by filtration and the filter cake washed withwater. The filter cake was then dissolved in 2000 ml. oftetrahydrofurane and the resulting solution dried. The tetrahydrofuranewas removed therefrom in vacuo leaving a thick red oil which wasextracted with three 1500 ml. portions of hot chloroform. The chloroformextracts were combined and the chloroform removed therefrom byevaporation in vacuo. The resulting residue comprising6-phenyl-1H-pyrrolo(1,2,3-de)quinoxaline-2,5(3H,6H)dione formed in theabove reaction melted at about 235°-35° C. after being recrystallizedfrom ethanol. A second recrystallization from chloroform yieldedcrystalline material melting in the range 241°-245° C., yield=6.3 g.

Analysis Calc.: C, 71.72; H, 4.50; N, 10.60; O, 12.11; Found: C, 71.81;H, 4.35; N, 10.10; O, 12.19.

Following the above procedure,4-(p-chlorophenyl-α-chloro)acetyl-3,4-dihydro-1H-quinoxalin-2-one wascyclized with polyphosphoric acid to yield6-(p-chloro)phenyl-1H-pyrrolo[1,2,3-de]quinoxalin-2,5(3H,6H)-dionemelting at 258°-64° C. with decomposition after recrystallization fromacetone.

Analysis Calc.: C, 64.66; H, 3.71; N, 9.38; O, 10.71; Cl, 11.87; Found:C, 64.66; H, 4.00; N, 9.04; O, 10.99; Cl, 11.59.

Following the above procedure,4-(p-fluorophenyl-α-chloro)acetyl-3,4-dihydro-1H-quinoxalin-2-one wascyclized with polyphosphoric acid to yield6-(p-fluoro)phenyl-1H-pyrrolo[1,2,3-de]quinoxalin-2,5(3H,6H)-dione whichmelted at 272°-75° C. with decomposition after recrystallization from amethanol-tetrahydrofurane solvent mixture.

Analysis Calc.: C, 68.08; H, 3.93; N, 9.92; F, 6.73; Found: C, 68.10; H,3.67; N, 9.68; F, 6.93.

Following the above procedure,4-(α,α-diphenyl-α-chloro)acetyl-3,4-dihydro-1H-quinoxalin-2-one wascyclized in polyphosphoric acid to yield6,6-diphenyl-1H-pyrrolo-[1,2,3-de]quinoxalin-2,5(3H,6H)-dione whichmelted at 235°-55° C. with decomposition after recrystallization frommethanol.

Analysis Calc.: C, 77.63; H, 4.74; N, 8.23; Found: C, 76.95; H, 4.64; N,7.64.

EXAMPLE 3 ALTERNATE PREPARATION OF6-PHENYL-1H-PYRROLO(1,2,3-de)-QUINOXALINE-2,5(3H,6H)-DIONE.

A mixture of 15 g. of4-α-phenyl-α-chloroacetyl-3,4-dihydro-1H-quinoxalin-2-one in 50 g. ofaluminum chloride were heated in the temperature in the range 180°-200°C. for about 30 minutes. The hot reaction mixture was poured into about1000 g. of an ice-water mixture. The resulting solid precipitate wasseparated by filtration and the filter cake washed with water.Recrystallization of the filter cake from chloroform yielded6-phenyl-1H-pyrrolo(1,2,3-de)quinoxaline-2,5(3H,6H)-dione melting at236°-40° C., after a second recrystallization from ethanol.

Analysis Calc.: C, 72.72; H, 4.58; N, 10.60; O, 12.11; Found: C, 72.20;H, 4.47; N, 10.33; O, 12.49.

EXAMPLE 4 PREPARATION OF1-ALKYL-6-PHENYL-1H-PYRROLO[1,2,3-de]-QUINOXALINE-2,5(3H,6H)-DIONES.

1. 1-Methyl-1H-quinoxalin-2-one was prepared by the method of Cheeseman,J. C. S., 1804, (1955). Using the same procedure,1-ethyl-1H-quinoxalin-2-one melting at 69°-71° C. was prepared.

Analysis Calc.: C, 68.95; H, 5.79; N, 16.08; Found: C, 68.81; H, 5.55;N, 15.95, and 1-n-propyl-1H-quinoxalin-2-one melting at 33°-48° C.,

Analysis Calc.: C, 70.19; H, 6.43; N, 14.88; Found: C, 70.03; H, 6.20;N, 14.68.

A mixture of 9.2 g. of 1-n-propyl-1H-quinoxalin-2-one and 3 g. of 5percent Pd/C in 200 ml. of THF were hydrogenated at 60 psi for 6 hours.The catalyst was separated by filtration and the filtrate evaporated todryness in vacuo. The residue, comprising1-n-propyl-3,4-dihydro-1H-quinoxalin-2-one formed in the above reaction,was crystallized from hexane and melted at 78°-80° C. (yield=7.4 g.)

Analysis Calc.: C, 69.45; H, 7.42; N, 14.73; Found: C, 69.70; H, 7.67;N, 14.67.

1-Methyl-3,4-dihydro-1H-quinoxalin-2-one was prepared by the sameprocedure and was an oil as was the corresponding 1-ethyl compound.

4-(α-Phenyl-α-chloro)acetyl derivatives of the above three1-alkyl-3,4-dihydro-1H-quinoxalin-2-ones were prepared by the method ofExample 1.4-(α-Phenyl-α-chloro)acetyl-1-methyl-3,4-dihydro-1H-quinoxalin-2-onemelted at 108°-111° C. after recrystallization from methanol.

Analysis Calc.: C, 64.87; H, 4.80; N, 8.90; Cl, 11.26; Found: C, 64.66;H, 4.51; N, 8.69; Cl, 11.54.

4-(α-Phenyl-α-chloro)acetyl-1-ethyl-3,4-dihydro-1H-quinoxalin-2-onemelted at 119°-123° C. after recrystallization from a benzene-hexanemixture.

Analysis Calc.: C, 65.75; H, 5.21; N, 8.52; Cl, 10.78; Found: C, 65.61;H, 5.27; N, 8.53; Cl, 11.04.

4-(α-Phenyl-α-chloro)acetyl-1-n-propyl-3,4-dihydro-1H-quinoxalin-2-onemelted at 105°-108° C. after recrystallization from a benzene-hexanesolvent mixture.

Analysis Calc.: C, 66.57; H, 5.59; N, 8.17; Cl, 10.34; Found: C, 66.30;H, 5.71; N, 8.10; Cl, 10.05.

Following the procedure of Example 2, each of the above4-(α-phenyl-α-chloro)acetyl derivatives was cyclized in the presence ofpolyphosphoric acid to yield the corresponding1H-pyrrolo[1,2,3-de]quinoxaline-2,5(3H,6H)-dione. The compounds thusprepared had the following characteristics:

1-Methyl-6-phenyl-1H-pyrrolo1,2,3-de]quinoxalin-2,5(3H,6H)-dione meltingat 142°-4° C. after recrystallization from ethanol.

Analysis Calc.: C, 73.37; H, 5.07; N, 10.07; Found: C, 73.34; H, 5.15;N, 10.04.

1-Ethyl-6-phenyl-1H-pyrrolo[1,2,3-de]quinoxalin-2,5(3H,6H)-dione meltingat 158°-61° C. after recrystallization from a benzene-acetone solventmixture.

Analysis Calc.: C, 73.95; H, 5.52; N, 5.58; Found C, 73.98; H, 5.54; N,9.33.

1-n-Propyl-6-phenyl-1H-pyrrolo[1,2,3-de]quinoxalin-2,5(3H,6H)-dionemelting at 147°-50° C. after recrystallization from methanol.

Analysis Calc.: C, 74.49; H, 5.92; N, 9.24; Found: C, 71.08; H, 5.65; N,8.32.

EXAMPLE 5 PREPARATION OF3-ALKYL-6-PHENYL-1H-PYRROLO[1,2,3-de]QUINOXALIN-2,5(3H,6H)-DIONES.

A mixture was prepared containing 20 of3-methyl-3,4-dihydro-1H-quinoxalin-2-one, 13.3 g. of triethylamine, and700 ml. of benzene. The mixture was heated to refluxing temperature and28 g. of α-acetoxy-α-phenylacetyl chloride in 80 ml. of benzene wasadded thereto. The resulting reaction was heated to refluxingtemperature for about 4 hours. The solids which precipitated during thisheating period were separated by filtration, and the filtrate wasevaporated to dryness in vacuo. The residue comprising4-(α-acetoxy-α-phenyl)acetyl-3-methyl-3,4-dihydro-1H-quinoxalin-2-oneformed in the above reaction was recrystallized from ethanol, melting at215°-218° C.; yield=19.3 g.

Analysis Calc.: C, 67.45; H, 5.36; N, 8.28; O, 19.18. Found: C, 67.73;H, 5.48; N, 8.36; O, 19.91.

A solution was prepared from 11 g. of4-(α-acetoxy-α-phenyl)acetyl-3-methyl-3,4-dihydro-1H-quinoxalin-2-one in200 ml. of ethanol. 20 ml. of water and 10 ml. of 1 N aqueous sodiumhydroxide were added and the resulting reaction mixture heated torefluxing temperature for about 3 hours. The pH of the solution was thenadjusted to about 6 with 1 N aqueous hydrochloric acid. The ethanol wasremoved from the aqueous solution in vacuo. The aqueous solution wasthen extracted three times with 200 ml. portions of chloroform. Thechloroform extracts were combined, dried, and the chloroform removedtherefrom by evaporation in vacuo. The residue comprising3-(α-hydroxy-2-phenyl)acetyl-3-methyl-3,4-dihydro-1H-quinoxalin-2-oneformed in the above reaction was recrystallized from a benzene-hexanesolvent mixture and melted below 120° C.; yield=5.4 g.

Analysis Calc.: C, 68.91; H, 5.44; N, 9.45; O, 16.20; Found: C, 68.76;H, 5.63; N, 11.31; O, 14.86.

Following the procedure of Example 3,4-(α-hydroxy-αphenyl)acetyl-3-methyl-3,4-dihydro-1H-quinoxalin-2-oneprepared in the above reaction was cyclized with polyphosphoric acid toyield 6-phenyl-3-methyl-1H-pyrrolo 1,2,3-de]quinoxalin-2,5(3H,6H)-dionemelting at 208°-211° C. after recrystallization from an ethanol-hexanesolvent mixture.

Analysis Calc.: C, 73.36; H, 5.07; N, 10.07; O, 11.50; Found: C, 73.13;H, 5.02; N, 10.07; O, 11.85.

Following the above series of reactions3-ethyl-3,4-dihydro-1H-quinoxalin-2-one was reacted with(α-acetoxy-αphenyl)acetyl chloride to yield the corresponding4-(α-acetoxy-α-phneyl)acetyl derivative, the acetyl group was removed bybasic hydrolysis, and the resulting α-hydroxy derivative cyclized withpolyphosphoric acid to yield6-phenyl-3-ethyl-1H-pyrrolo[1,2,3-de]quinoxalin-2,5(3H,6H)-dione meltingat 205°-208° C. after recrystallization from methanol.

Analysis Calc.: C, 73.95; H, 5.52; N, 9.50; O, 10.95; Found: C, 73.83;H, 5.32; N, 9.80; O, 11.09.

EXAMPLE 6 ALTERNATE PREPARATION OF6-PHENYL-1H-PYRROLO[1,2,3-de]-QUINOXALIN-2,5(3H,6H)-DIONE.

Following the procedure of Example 5, 3,4-dihydro-1H-quinoxalin-2-onewas reacted with (α-acetoxy-α-phenyl)acetyl H-quinoxalin-2-one whichmelted at 156°-158° C. after recrystallization from methanol.

Analysis Calc.: C, 66.66; H, 4.91; N, 8.64; O, 19.73; Found: C, 66.57;H, 4.92; N, 8.45; O, 19.53.

The above acetoxy compound was hydrolyzed to the4-(α-hydroxy-α-phenyl)acetyl.Iadd.-3-methyl.Iaddend.-3,4-dihydro-1H-quinoxalin-2-oneas follows: 56 g. of4-(α-acetoxy-α-phenyl)acetyl-3,4-dihydro-1H-quinoxalin-2-one weredissolved in 350 ml. of methanol. 10 ml. of diisopropyl ethylamine wereadded and the resulting mixture refluxed for about 18 hours. The solventwas removed in vacuo and the resulting residue, comprising4-(α-hydroxy-α-phenyl)acetyl.Iadd.-3-methyl.Iaddend.-3,4-dihydro-1H-quinoxalin-2-oneformed in the above reaction, was recrystallized from a benzene-ethanolsolvent mixture; melting point=177°-178° C.; yield=36.5 g.

Analysis Calc.: C, 68.08; H, 5.00; N, 9.92; O, 17.00; Found: C, 67.80;H, 4.76; N, 9.71; O, 17.27.

36 g. of the above 4-(α-hydroxy-α-phneyl)acetyl derivative was cyclizedin 800 g. of polyphosphoric acid to yield6-phenyl-1H-pyrrolo[1,2,3-de]quinoxalin-2,5(3H,6H)-dione, which had thephysical characteristics previously set forth.

EXAMPLE 7 PREPARATION OF8-SUBSTITUTED-6-PHENYL-1H-PYRROLO[1,2,3-de]QUINOXALIN-2,5(3H,6H)-DIONES.

N-(2-nitro-4-chlorophenyl)-glycine was prepared by the procedure of J.Chem. Soc., 1260 (1949) and the substituted glycine cyclized to yield7-chloro-3,4-dihydro-1H--one utilizing a procedure also set forth inthat reference. The reaction of 7-chloro-3,4-dihydro-1H-quinoxalin-2-onewith α-chloro-α-phenylacetyl chloride by the procedure of example 1yielded4-(α-phenyl-α-chloro)-acetyl-7-chloro-3,4-dihydro-1H-quinoxalin-2-onemelting at 164°-7° C. after recrystallization from methanol.

Analysis Calc.: C, 57.33; H, 3.61; N, 8.36; Cl, 21.15; Found: C, 57.14;H, 3,77; N, 8.65; Cl, 21.25.

Cyclization of this compound by the procedure of either Example 2 orExample 3 gave6-phenyl-8-chloro-1H-pyrrolo[1,2,3-de]quinoxalin-2,5(3H,6H)-dionemelting at 258°-63° C. with decomposition after recrystallization frommethanol.

Analysis Calc.: C, 64.33; H, 3.71; N, 9.38; Cl, 11.87; Found: C, 64.55;H, 3.85; N, 9.25; Cl, 12.14.

Following the above procedure, 7-methoxy-3,4-dihydro-1H-quinoxalin-2-onewas prepared from N-(2-nitro-4-methoxyphenyl)glycine, the lattercompound being prepared according to the procedure set forth in J. Chem.Soc., 1271, (1949).4-(α-Phenyl-α-chloro)acetyl-7-methoxy-3,4-dihydro-1H-quinoxalin-2-onethus prepared melted at 156°-59° C. after recrystallization frommethanol.

Analysis Calc.: C, 61.54; H, 4.86; N, 8.44; Cl, 10.69; Found: C, 61.60;H, 4.70; N, 8.67; Cl 9.11.

Cyclization of the α-chloroacetyl derivative to6-phenyl-8-methoxy-1H-pyrrolo[1,2,3-de]quinoxalin-2,5(3H,6H)-dione wascarried out according to the procedure of Example 2. The compound meltedat 234°-7° C. with decomposition after recrystallization from methanol.

Analysis Calc.: C, 69.63; H, 4.79; N, 9.52; O, 16.31; Found: C, 69.26;H, 4.97; N, 9.33; O, 16.10.

Following the procedure of J. Chem. Soc. 1260, 1271 (1949)N-[2-nitro-4-(p-fluoro)phenyl]glycine was prepared melting at 202°-205°C. with decomposition.

Analysis Calc.: C, 44.87; H, 3.29; N, 13.08; Found: C, 45.14; H, 3.52;N, 12.94.

Cyclization to 7-fluoro-3,4-dihydro-1H-quinoxalin-2-one was carried outby the procedure of the same article. The compound melted at 214°-17° C.with decomposition after recrystallization from a benzene-THF solventmixture.

Analysis Calc.: C, 57.83; H, 4.25; N, 16.86; F, 11.43; Found: C, 57.64;H, 4.18; N, 16.60; F, 11.15.

7-Fluoro-4(α-hydroxy-2-phenyl)acetyl-3,4-dihydro-1H-quinoxalin-2-one wasprepared by the above method. It melted at 165°-7° C. afterrecrystallization from a benzene-methanol solvent mixture.

Analysis Calc.: C, 64.00; H, 4.36; N, 9.33; F, 6.33; Found: C, 63.76; H,4.22; N, 9.45; F, 6.20.

The 4-acetylderivative was cyclized by polyphosphoric acid to yield6-phenyl-8-fluoro-1H-pyrrolo[1,2,3-de]quinoxaline-2,5(3H,6H)-dione asset forth above. The compound melted at 205°-8° C. afterrecrystallization from benzene.

Analysis Calc.: C, 68.08; H, 3.93; N, 9.92; F, 6.73; Found: C, 68.27; H,4.16; N, 10.08; F, 6.78.

The same sequence of reaction was carried out to prepare the 8-methylderivatives. N-[2-Nitro-4-(p-methyl)-phenyl]glycine was prepared by themethod of J.A.C.S. 1260 (1949) and melted at 184°-6° C.

Analysis Calc.: C, 51.43; H, 4.80; N, 13.30; Found: C, 51.69; H, 4.04;N, 13.57.

7-Methyl-3,4-dihydro-1H-quinoxalin-2-one prepared therefrom melted at129°-31° C. after recrystallization from an ethanol-water solventmixture.

Analysis Calc.: C, 66.65; H, 6.21; N, 17.27; Found: C, 66.38; H, 6.41;N, 17.19.

4-(α-Chloro-α-phenyl)acetyl-7-methyl-3,4-dihydro-1H-quinoxalin-2-oneprepared therefrom was cyclized directly (without further purification)using polyphosphoric acid by the procedure of Example 2 to yield6-phenyl-8-methyl-1H-pyrrolo[1,2,3-de]quinoxalin-2,5(3H,6H)-dionemelting at 195°-200° C. with decomposition after recrystallization fromethanol.

Analysis Calc.: C, 73.37; H, 5.07; N, 10.07; Found: C, 73.17; H, 5.27;N, 9.85.

EXAMPLE 8 PREPARATION OF6-PHENYL-1H-BENZO[g]PYRROLO[1,2,3-de]-QUINOXALIN-2,3(3H,6H)-DIONE.

A solution of 20 g. of 2,3-diaminonaphthalene in 400 ml. of ethanol wasprepared. A solution of 11.6 g. of thereto and the resulting reactionmixture heated at refluxing temperature for about 4 hours. The solidquinoxalinone which precipitated upon cooling was collected byfiltration and the filter cake washed with ethanol. Recrystallization ofthe filter cake from THF yielded 6,7-benzo-1H-quinoxalin-2-one meltingat 334°-338° C. with decomposition, (yield=12.2 g).

Analysis Calc.: C, 73.46; H, 4.11; N, 14.88; O, 8.15; Found: C, 73.15;H, 3.98; N, 14.13; O, 7.81.

A hydrogenation mixture was prepared containing 12 g. of6,7-benzo-1H-quinoxalin-2-one, 3 g. of 5 percent of Pd/C and 270 ml. ofDMF. The mixture was hydrogenated at 60 psi for 6 hours after which timethe catalyst was removed by filtration and the filtrate evaporated todryness in vacuo. 6,7-Benzo-3,4-dihydro-1H-quinoxalin-2-one thus formedremained as a residue and melted at 267°-70° C. with decomposition afterrecrystallization from THF. Yield=8.3 g.

Analysis Calc.: C, 72.71; H, 5.09; N, 14.13; O, 8.07; Found: C, 72.76;H, 4.87; N, 14.34; O, 8.18.

Following the procedure of Example 1, the above quinoxalinone wasreacted with α-chloro-α-phenylacetyl chloride by the procedure ofExample 1 to yield4-(α-chloro-α-phenyl)acetyl-6,7-benzo-3,4-dihydro-1H-quinoxalin-2-onewhich melted at 198°-200° C. with decomposition after recrystallizationfrom methanol.

Analysis Calc.: C, 64.48; H, 4.31; N, 7.99; Cl, 10.11; Found: C, 68.35;H, 4.14; N, 8.12; Cl, 9.92.

Following the procedure of Example 2, the above α-chloroacetylamide wascyclized with polyphosphoric acid to yield6-phenyl-1H-benzo[g]pyrrolo[1,2,3-de]quinoxalin-2,5(3H,6H)-dione whichmelted at 296°-300° C. with decomposition after recrystallization fromTHF.

Analysis Calc.: C, 76.42; H, 4.49; N, 8.91; Found: C, 76.14; H, 4.46; N,8.87.

EXAMPLE 9 PREPARATION OF2,3-DIHYDRO-6-PHENYL-1H-PYRROLO[1,2,3-de]QUINOXALIN-5(6H)-ONE.

A solution was prepared containing 7 g. of 1,2,3,4-tetrahydroquinoxalineprepared by the procedure of J. Am. Chem. Soc., 69, 797 (1947) and 5.2g. of triethylamine in 750 ml. of benzene. A solution of 11.12 g. ofα-acetyl-mandeloyl chloride in 100 ml. of benzene was added thereto. Theresulting mixture was stirred at ambient temperature for about 6 hours.Solids which formed during the reaction were separated by filtration andthe filtrate was evaporated to dryness in vacuo. The residue comprising4-(α-acetoxy-α-phenyl)acetyl-1,2,3,4-tetrahydroquinoxaline formed in theabove reaction was recrystallized from a benzene-hexane solvent mixtureand melted at 125°-7° C. (yield=13.2 g.).

Analysis Calc.: C, 69.66; H, 5.85; N, 9.03; Found: C, 69.59; H, 5.95; N,8.88.

5 Gms. of 4-(α-acetoxy-α-phenyl)acetyl-1,2,3,4-tetrahydroquinoxaline wasadded to 15 ml. of 18 M sulfuric acid kept in an oil bath at about 76°C. The resulting mixture was stirred for 30 minutes and was then pouredinto 200 g. of ice. The pH of the resulting solution was adjusted toabout 7 with 5 N aqueous sodium hydroxide. The neutral aqueous solutionwas extracted twice with 300 ml. of ethyl acetate. The ethyl acetateextracts were separated, combined, washed with water and dried. Removalof the ethyl acetate in vacuo yielded a residue comprising2,3-dihydro-6-phenyl-1H-pyrrolo[1,2,3-de]quinoxalin-5(6H)-one whichmelted at about 168°-71° C. after recrystallization from methanol;yield=2.3 g.

Analysis Calc.: C, 76.78; H, 5.64; N, 11.19; O, 6.39; Found: C, 76.47;H, 5.64; N, 10.86; O, 6.85.

EXAMPLE 10 PREPARATION OF3,4-DIHYDRO-7-PHENYL-1H-PYRROLO[1,2,3-ef]BENZO-[f]DIAZEPINE-2,6(1H,7H)-DIONE.

3,4-Benzo(f)diazepin-2-one, prepared by the method of J. Amer. Chem.Soc., 71, 1986 (1949), was reacted with α-chloro-α-phenylacetyl chlorideto yield the corresponding 5-(α-chloro-α-phenyl)acetyl derivative whichmelted at 206°-209° C. after recrystallization from methanol.

Analysis Calc.: C, 64.87; H, 4.80; N, 8.90; O, 10.17; Cl, 11.26; Found:C, 65.07; H, 4.87; N, 9.13; O, b 9.99; Cl, 11.36.

Following the procedure of Example 3, the above α-chloro-α-phenylacetylderivative was cyclized with aluminum chloride to yield3,4-dihydro-7-phenyl-1H-pyrrolo[1,2,3-ef][1,5]benzo(f)diazepin-2,6-(1H,7H)-dionemelting at 222°-226° C. after recrystallization from methanol.

Analysis Calc.: C, 73.37; H, 5.07; N, 10.07; O, 11.50; Found: C, 73.20;H, 5.17; N, 9.97; O, 11.51

EXAMPLE 11 PREPARATION OF6-HYDROXY-6-PHENYL-1H-PYRROLO[1,2,3-de]QUINOXALIN-2,5(3H,6H)-DIONE.

A solution was prepared containing 235 g. of sodium sulfite and 37 g. ofchloral hydrate in 600 ml. of water. A solution of 30 g. of3,4-dihydro-1H-quinoxalin-2-one in 200 ml. of water was added theretofollowed by about 30 ml. of 12 N aqueous hydrochloric acid. Next, 42 g.of hydroxylamine hydrochloride dissolved in 100 ml. of water was addedthereto and the final reaction mixture was heated until refluxingtemperature was achieved. The reaction mixture was then cooled in an icebath. The solid that precipitated comprising4-isonitrosoacetyl-3,4-dihydro-1H-quinoxalin-2-one formed in the abovereaction, was separated by filtration. The filter cake was dissolved in2000 ml. of chloroform. The chloroform solution was dried and thechloroform removed therefrom in vacuo. The resulting residue, comprisingthe isonitrosoacetyl derivative, was recrystallized from ethanol-benzenesolvent mixture and melted at 202°-204° C.; yield=4.2 g.

Analysis Calc.: C, 54.54; H, 4.58; N, 19.08; O, 21.80; Found: C, 54.74;H, 4.32; N, 19.09; O, 21.54.

18 ml. of 18 M sulfuric acid were heated to about 60° C. in an oil bath.4 g. of 4-isonitrosoacetyl-3,4-dihydro-1H-quinoxalin-2-one were addedthereto while maintaining the temperature in the range 60°-70° C. Theresulting mixture was then heated at 80° C. for 30 minutes, after whichtime the reaction mixture was poured into 200 g. of ice. The solid whichprecipitated, comprising1H-pyrrolo[1,2,3-de]quinoxalin-2,5,6-(3H)-trione formed in the abovereaction, was separated by filtration and the filter cake washed withwater. The filter cake was recrystallized from methanol yieldingcrystalline material melting at 294°-8° C. with decomposition.

Analysis Calc.: C, 59.41; H, 2.99; N, 13.06; O, 23.74; Found: C, 59.32;H, 3.01; N, 14.05; O, 23.44.

A suspension was prepared from 4.3 g. of1H-pyrrolo[1,2,3-de]quinoxalin-2,5,6(3H)-trione in 200 ml. of THF. 16ml. of 2.83 M phentlmagnesium bromide solution in diethyl ether (phenylGrignard reagent) were added thereto while maintaining the temperaturein the range 10°-15° C. The resulting reaction mixture was stirredovernight after which time, 200 ml. of a saturated aqueous amoniumchloride solution were added. An additional 1500 ml. of diethyletherwere added and the ethereal layer decanted from the solids. The ethereallayer was dried and the ether removed therefrom in vacuo. The resultingresidue, comprising6-hydroxy-6-phenyl-1H-pyrrolo[1,2,3-de]quinoxalin-2,5(3H,6H)-dionemelted at 259°-62° C. with decomposition after recrystallization frommethanol; yield=2.4 g.

Analysis Calc.: C, 68.56; H, 4.32; N, 9.99; O, 17.12; Found: C, 68.29;H, 4.10; N, 10.22; O, 16.86.

The compounds of this invention are anti-inflammatory andanti-thrombotic agents. Their anti-inflammatory activity can bedemonstrated by their ability to block the erythema produced by anultra-violet light source on guinea pig skin according to the method ofWindner, et al. Arch. Int. Pharmacodyn, 116, 261 (1958). In thisprocedure, albino guinea pigs weighing 225-300 gms. are shaved on theback and chemically depilated 18 to 20 hours before initiation of thetest procedures. Animals in groups of 4 are given predetermined dosagesof the drug under test with one group being maintained as a controlgroup. The drug is administered by the oral route as a suspension in 1percent aqueous sodium carboxymethylcellulose. The control animalsreceive only the suspending media. After having being given the drug orsuspension medium only, each group of animals is exposed to ahigh-intensity ultra-violet light for a predetermined period of time,the ultra-violet light being placed in contact with the depilated skinarea on the animals' back. A gummed paper reinforcement is affixed tothe lamp lens to provide an unexposed area of contrast for grading thelight-produced erythema.

Beginning one hour after exposure and thereafter at half-hour intervalsfor another 1.5 hours, a trained observer grades erythema using anarbitraty scoring system based upon the degree of contrast and rednessformed. The scores are weighted by factors of 4,3,2, and 1 at the 0.0,1.5, 2.0 and 2.5 hour scoring times respectively becauseanti-inflammatory agents are usually less effective with the passage oftime. The following scoring system is used:

    ______________________________________                                        Score         Appearance of Exposed Area                                      ______________________________________                                        0             No redness and no contrast                                      1             Slight redness with a faint                                                   reinforcement outline                                           2             Slight to moderate redness                                                    with a distinct outline                                         3             Marked redness with a distinct                                                circular outline                                                ______________________________________                                    

Total scores from each treatment group of four guinea pigs are comparedto the control treatment, and the percent inhibition calculated asfollows: ##EQU1##

If desired, a dose-response graph can be obtained by plotting doseversus percent inhibition, each point representing the average of onetreatment group of four guinea pigs. The dose (ED₅₀) in mg/kg whichproduced a 50 percent inhibition of the erythemic response for theparticular compound tested can then be obtained, either directly or byextrapolation. Table I below summarizes the results obtained fromtesting representative compounds of the invention by the foregoingmethod.

Certain of the compounds of this invention are also platelet aggregationinhibitors and the results of testing for this activity are alsoincluded in Table I. The platelet aggregation test used involves theeffect of a drug upon collagen-induced platelet aggregation using themethod of Hermann et al., Proc. Soc. Exp. Biol. Med. 136, 548 (1972).According to this procedure, 300-400 g. guinea pigs are used and thecompound is administered by the oral route in 2 doses, at time zero andagain 2 hours later, at a series of graded dose levels to groups of 4pigs each. One group is maintained as a control group. Blood is removedby heart puncture 60 minutes after the last dose, and a platelet-richplasma prepared therefrom. A stock collagen solution is prepared bysolubilizing bovine Achilles tendon with acetic acid. The stock solutioncontains 0.25 percent collagen, has a pH of 2.8 and is kept underrefrigeration. Prior to use, 0.4 ml. of 1 M aqueous sodium hydroxide isadded to a 1 ml. aliquot of the stock solution, followed by furtherdilutions with saline (1:2, 1:4, 1:8, 1:16, 1:32, etc.) A standardcollagen challenge was used, 0.05 ml. of 1:45 dilution, to induceplatelet aggregation and the aggregation response of the drugged guineapigs was compared to that of the controls to determine inhibition ofaggregation. The lowest active dose in mg./kg.×2 is then determined,"active" being defined as giving about 50% inhibition ofcollagen-induced aggregation. (Activity was determined by computorprintout with significance at the 95 percent confidence level beingattained at about the 50 percent inhibition level). These lowesteffective dose levels are also given in Table 1 which follows. In Table1, column 1 gives the name of the compound, column 2, the ED₅₀calculated as set forth above and column 3, the percent inhibition at a50 mg/kg dose level where an ED₅₀ was not determined and column 4, thelowest active dose in the platelet aggregation test. N. A. indicates"not active" at 100 mg/kg×2 in this latter test.

                                      Table 1                                     __________________________________________________________________________                              ED.sub.50                                                                          Inhibition at                                                                         P.A.                                   Name of Compound          in mg/kg                                                                           50 mg/kg dose                                                                         mg/kg × 2                        __________________________________________________________________________    1-methyl-6-phenyl-1H-pyrrolo[1,2,3-de]                                        quinoxalin-2,5(3H,6H)-dione                                                                             4.4          3.12                                   6-phenyl-1H-pyrrolo-[1,2,3-de]quinoxalin-                                     2,5(3H,6H)-dione          0.9          1.56                                   1-ethyl-6-phenyl-1H-pyrrolo-[1,2,3-de]-                                       quinoxalin-2,5(3H,6H)-dione                                                                             33           100                                    1-n-propyl-6-phenyl-1H-pyrrolo-[1,2,3-de]-                                    quinoxalin-2,5(3H,6H)-dione                                                                             47.5                                                6-phenyl-8-methyl-1H-pyrrolo-[1,2,3-de]-                                      quinoxalin-2,5(3H,6H)-dione    51%     3.12                                   6-phenyl-8-methoxy-1H-pyrrolo-[1,2,3-de]quinoxalin-                           2,5(3H,6H)-dione          45           6.25                                   6-phenyl-8-chloro-1H-pyrrolo-[1,2,3-de]quinoxalin-                            2,5(3H,6H)-dione               50%     100                                    6-phenyl-1H-benzol[2]-pyrrolo-[1,2,3-de]-                                     quinoxalin-2,5(3H,6H)-dione    42%     NA                                     3-methyl-6-phenyl-1H-pyrrolo-[1,2,3-de]quinoxalin-                            2,5(3H,6H)-dione          2.5          1.56                                   3-ethyl-6-phenyl-1H-pyrrolo-[1,2,3-de]quinoxalin-                             2,5(3H,6H)-dione          1.0          50                                     6-(4-fluorophenyl)-1H-pyrrolo[1,2,3-de]-                                      quinoxalin-2,5(3H,6H)-dione                                                                             7.7          12.5                                   6-(4-chlorophenyl)-1H-pyrrolo[1,2,3-de]                                       quinoxalin-2,5(3H,6H)-dione    48%                                            3,4-dihydro-7-phenyl-1H-pyrrolo[1,2,3-ef]-                                    benzo-[f]-diazepin-2,6(1H,7H)-dione                                                                     12           50                                     2,3-dihydro-6-phenyl-1H-pyrrolo[1,2,3-de]-                                    quinoxalin-5(3H)-one      7.9          100                                    6,6-diphenyl-1H-pyrrolo[1,2,3-de]-quinoxalin-                                 2,5-(3H,6H)-dione         36                                                  __________________________________________________________________________

As anti-inflammatory agents, the compounds of this invention can beadministered to mammals suffering from inflammation, either orally orparenterally, and in the case of inflammation of body surface, bytopical application.

The amount of the compound or compounds employed is not critical so longas an effective, anti-inflammatory amount is used. In general,anti-inflammatory activity is exhibited at doses of from 0.01 to 50 ormore mg/kg. of animal body weight.

In carrying out the anti-inflammatory methods of the present invention,it is generally preferred to employ a composition comprising the activeagent and one or more adjuvants suited to the particular route ofadministration. Compositions for oral administration may be eithersolid, e.g., capsules, tablets, pills, powders, etc., or liquids, e.g.,emulsions, solutions, suspensions, syrups, elixirs, etc. Inasmuch assome of the compounds to be employed as active agent are liquids, softelastic gelatin capsules are often suitable employed for oraladministration. In any of these various forms, the active agent can becombined with conventional adjuvants. In the case of solid formulations,suitable adjuvants include inert substances such as sucrose, lactose,and starch. In the case of liquid formulations, suitable adjuvantsinclude water, mineral oil, etc. Either solid or liquid formulation caninclude lubricating agents, wetting agents, emulsifying and suspendingagents, preserving agents, sweetening agents, flavoring agents, orperfuming agents.

In the instance of parenteral administration, the compounds of thepresent invention are formulated in a suitable sterile, injectableliquid.

Formulations suitable for topical administration include lotions,ointments, creams, spray, etc. Conventional adjuvants are employed.

In general, oral administration is preferred. Accordingly, a preferredformulation is a pharmaceutical preparation in dosage unit form adaptedfor administration to obtain an anti-inflammatory effect, comprising,per dosage unit, an effective non-toxic amount within the range fromabout 1 to about 1000 milligrams of one or more of the compounds or thisinvention. For many applications, the above preparation may suitablycontain only a lesser amount of active agent, such as from about 5 toabout 500 milligrams, or an even lesser amount of active agent, such asfrom about 25 to about 125 milligrams.

In employing those compounds of this invention which haveanti-thrombotic activity in the treatment of vascular thrombosis, itshould be emphasized that such treatment is customarily prophylactic innature. Thus, there is administered to an individual an amount of drugbased upon his need for such administration. In general, an individualwill require treatment with an anti-thrombotic agent under either of twosituations: (1) the individual already has suffered overt manifestationsof a thromboembolic disease, or (2) the individual has an identifiablerisk of contracting a thromboembolic disease but has not yet shown anyovert manifestations of such disease. In either case, the prophylactictreatment of the individual with an anti-thrombotic agent is intended toprevent further thromboembolic disease in the individual or, at least,to minimize the effects of such disease. For prophylaxis of incipient orover thromboembolic disease, the oral route of administration ispreferred, utilizing the oral dosage forms set forth above.

I claim:
 1. A compound of the formula: ##STR5## wherein R' is H or C₁-C₃ alkyl;when taken singly, R² is H, C₁ -C₃ alkyl, C₁ -C₃ alkoxy,.Iadd.F .Iaddend.or Cl and R³ is H; and R² and R³ when taken togetherwith the carbon atoms to which they are attached form a benzene ring; R⁴is H, Cl or F; R⁵ is OH, H or phenyl; Y is O or H₂ ; Z is --CH₂ --CH₂ --or --CHR⁶ -- wherein R⁶ is H or C₁ -C₃ alkyl.
 2. A compound according toclaim 1 in which R', R², R³, R⁴ and R⁵ are H, Z is CHR⁶, R⁶ is H and Yis O, said compound being6-phenyl-1H-pyrrolo[1,2,3-de]quinoxalin-2,5(3H,6H)-dione.
 3. A compoundaccording to claim 1 in which R', R², R³, R⁴ and R⁵ are H, Z is CHR⁶, R⁶is C₁ -C₃ alkyl and Y is O.
 4. A compound according to claim 3 in whichR⁶ is ethyl, said compound being3-ethyl-6-phenyl-1H-pyrrolo-[1,2,3de]quinoxalin-2,5(3H,6H)-dione.
 5. Acompound according to claim 3 in which R⁶ is methyl, said compound being3-methyl-6-phenyl-1H-pyrrolo-[1,2,3-de]quinoxalin-2,5(3H,6H)-dione.
 6. Acompound according to claim 1 in which R' is C₁ -C₃ alkyl, R², R³, R⁴and R⁵ are H, Z is CHR⁶, R⁶ is H and Y is O.
 7. A compound according toclaim 6 in which R' is methyl, said compound being1-methyl-6-phenyl-1H-pyrrolo-[1,2,3-de]quinoxalin-2,5(3H,6H)-dione.
 8. Acompound according to claim 6 in which R' is ethyl, said compound being1-ethyl-6-phenyl-1H-pyrrolo-[1,2,3-de]quinoxalin-2,5(3H,6H)-dione.